Maytansine is a compound found to have anticancer properties but is clinically proven to be too toxic to use in humans. Maytansine is an ansamycin antibiotic isolated from various species of the genus Maytenus, spiny shrubs that grow in many parts of Africa, and shows significant in vivo tumor inhibitory activity. (Kupchan et al. (February 1972), “Maytansine, a Novel Antileukemic Ansa Macrolide from Maytenus ovates,” Journal of the American Chemical Society 94(4):1354-1356.) Maytansine is believed to bind to tubulin at the rhizoxin binding site, thereby inhibiting microtubule assembly, inducing microtubule disassembly, and disrupting mitosis. Maytansine is a highly cytotoxic natural product that fails as an anticancer agent in human clinical trials because of unacceptable systemic toxicity.
Maytansinoids are derivatives of maytansine and are potent antitumor agents found in plants and microorganisms. Maytansinoids and maytansinoid analogs with potential as anticancer drugs have been previously described in Kupchan et al. (1978), “Structural Requirements for Antileukemic Activity among the Naturally Occurring and Semisynthetic Maytansinoids,” Journal of Medicinal Chemistry 21(1):31-37; and in WO 2005/099754. Existing maytansinoids mostly contain a single macrocyclic ring, although a handful of maytansinoids having two macrocyclic rings are known. (Larson et al. (1999), “Two New Maytansinoids from Maytenus buchananii,” 62(2):361-363; and Cassady et al. (2004), “Recent Developments in the Maytansinoid Antitumor Agents,” Chem. Pharm. Bull. 52(1):1-26.) Two such maytansinoids, trenudine and treflorine, which contain two fused macrocyclic rings, retain antitumor activity against KB cells and P388 lymphocytic leukemia. (Powell et al. (1982), Journal of the American Chemical Society 104(18): 4929-34.)
It is a goal of the present invention to provide new maytansinoid compounds having improved antitumor activity and/or having reduced systemic toxicity in humans for cancer treatment.